Bonnie N. Dittel, Ph.D.

Investigator
Blood Research Institute
BloodCenter of Wisconsin

Assistant Adjunct Professor
Department of Microbiology and Molecular Genetics
Medical College of Wisconsin

Postdoctoral Training
Yale University

Doctoral Training
University of Minnesota
Ph.D. 1994

Selected Publications
Grant Support
Laboratory Staff
Contact Information

Research Interest
The goal of my research program is to investigate the cellular and molecular mechanisms involved in the regulation of the immune response. My laboratory has two primary lines of investigation. First, we are studying how the immune system regulates inflammation associated with autoimmunity in the central nervous system (CNS) (brain and spinal cord). Secondly, we are studying memory T cell repertoires in the blood and lungs of influenza-infected individuals and are developing a model of influenza-specific memory T cell generation in mice. Both of these studies are centered on understanding how the immune system functions in tissues.

CNS Inflammation

To study the regulation of inflammation associated with an autoimmune attack in the CNS, we are using the rodent model of the human autoimmune disease multiple sclerosis (MS), termed experimental autoimmune encephalomyelitis (EAE). Autoimmunity is a serious immunological disorder with devastating clinical consequences and occurs when a person’s own immune system inappropriately reacts against their own tissues. In the case of MS, which is thought to be an autoimmune disease of the CNS, patients mount a T cell response against protein found in the myelin sheath covering nerve axons. MS patients exhibit a wide variety of neurological symptoms, including muscle weakness and changes in vision and memory. In the study of MS, advances in understanding the disease process have been facilitated using the EAE model. EAE is a CD4 T cell-mediated autoimmune disease and like MS is characterized by the accumulation of immune cells in the CNS.

EAE Initiation and Microglial Cell Activation
In our studies examining initiation of EAE disease, we have extensively studied the role of microglial cells and how they become activated by self-reactive T cells. Microglial cells are from the monocytic lineage and are resident to the CNS existing in a resting state characterized by a ramified morphology. However, upon activation, microglial cells alter both their morphology and phenotype. We have found that microglial cells can differentiate into cells resembling both macrophages and microglial cells. Macrophages are phagocytic and can remove dying cells, while the primary function of dendritic cells is the presentation of antigens to T cells. In addition, we found that microglial cells become activated prior to the migration of macrophages from the blood into the CNS, suggesting that microglial activation is essential for the onset of EAE. Currently, we are studying how encephalitogenic T cells microglial cell activation. We have also developed a culture system to grow adult microglial cells in the laboratory.

T Cell-Neuronal Interactions
Although both EAE and MS are considered to be demyelinating diseases, not all of the clinical symptoms can be explained by just the loss of the myelin sheath in localized lesions. Indeed, it is known that damage to the nerves themselves can be observed in both MS and EAE. Thus we are studying whether the encephalitogenic T cells may directly interact with neurons. Our preliminary studies show that they do, resulting in neuronal dysfunction. We are currently investigating the mechanism of the interaction and dysfunction using neurons that express a fluorescent protein.

T Cell-Neuronal Interactions
Although both EAE and MS are considered to be demyelinating diseases, not all of the clinical symptoms can be explained by just the loss of the myelin sheath in localized lesions. Indeed, it is known that damage to the nerves themselves can be observed in both MS and EAE. Thus we are studying whether the encephalitogenic T cells may directly interact with neurons. Our preliminary studies show that they do, resulting in neuronal dysfunction. We are currently investigating the mechanism of the interaction and dysfunction using neurons that express a fluorescent protein.

Cannabinoid System
We are also examining the role of the endogenous cannabinoid system in the CNS during EAE. The cannabinoid system was first discovered because the active ingredient in marijuana, THC, binds to receptors in the brain. Now it is known that cannabinoids are produced in the brain and throughout the body. We are studying how the cannabinoid system regulates inflammation in the CNS.

Memory T cells in Influenza Infection
The newest project in the laboratory is investigating the generation and maintenance of memory T cells specific for the virus that causes the flu. Every year new strains of the influenza virus arise requiring the development of new vaccines. Even though the influenza virus infects the lung, surprisingly little is known about the T cell populations that reside in the lungs of healthy individuals and those suffering from the flu. This project will examine the T cell receptor repertoire of the T cells in the lung and compare them to those circulating in the blood. In addition, we will be developing a mouse model of influenza using humanized mice.

The primary focus of my laboratory is to understand how T cells regulate immune responses during autoimmunity and viral infections. This work is important to the development of new treatment strategies for diseases that are very devastating for those inflicted.

Selected Publications

• Ponomarev, E.D., M. Novikova, M. Yassai, M. Szczepanik, J. Gorski, and B.N. Dittel. 2004. γδ T cell regulation of IFN-γ production by CNS infiltrating encephalitogenic T cells: Correlation with recovery from experimental autoimmune encephalomyelitis. J. Immunol. 173:1587-1595.
• Ponomarev, E.D. and B.N. Dittel. 2005. γδ T cells regulate the extent and duration of inflammation in the CNS by a FasL-dependent mechanism. J. Immunol. 174:4678-4687.
• Ponomarev, E.D., M. Novikova, K. Maresz, L.P. Shriver, and B.N. Dittel. 2005. Development of a culture system that supports adult microglial cell proliferation and maintenance in the resting state. J. Immunol. Meth. 300:32-46.
• Ponomarev, E.D., L.P. Shriver, K. Maresz, and B.N. Dittel. 2005. Microglial cell activation and proliferation precedes the onset of CNS Autoimmunity. J. Neurosci Res. 81:374-389.
• Maresz, K., E.J. Carrier, E.D. Ponomarev, C.J. Hillard, and B.N. Dittel. 2005. Modulation of the endocannabinoid CB2 receptor in microglial cells in response to inflammatory stimuli. J. Neurochem. 95:437-445.
• Ponomarev, E.D., L.P. Shriver and B.N. Dittel. 2006. CD40 expression by microglial cells is required for their completion of a two-step activation process during CNS autoimmune inflammation. J. Immunol. 176:1402-1410.

Grant Support

• NIAID R01 AI69358-01A2, "The Role of B Cells in Regulating Autoimmunity"
• NINDS R01 NS046662-01A1, “Encephalitogenic T cell regulation of microglial cells”
• NIAID U19 A162627-01, NIH, “Robust T-cell immunity to Influenza in Human Populations” PI project 3: “Alpha/Beta and Gamma/Delta T cell Mediated Immunity in Influenza Infection in the Lung”
• National Multiple Sclerosis Society, RG 3550A3/1, “Interactions between encephalitogenic T cells and neurons”
• NIAID N01-AI-500032, “Generation and decay of memory T cells in young, old and immunocompromised populations” PI Objective 4: “Model the effect of immunosuppression on memory repertoire formation using normal and autoimmune HLA transgenic mice.”

Laboratory Staff
 

Employment Opportunities
If opportunities are available, they will be listed on the Employment page.

Contact Information
Phone: (414) 937-3865
Fax: (414) 937-6284
E-mail: bonnie.dittel@bcw.edu